The present invention relates to a method of treating a mammal in order to inhibit metastatic spread in surgical extirpation of a cancer mass, using 1-deamino-8-D-arginine vasopressin (desmopressin).
In spite of the continuous advances in surgical techniques and of the development of adjuvant intensive therapeutics to treat neoplastic diseases, the vast majority of deaths caused by cancer is related to metastatic dissemination.
European Patent Publication EP 380370 discloses local recurrence inhibition of a tumor surgical resection of the application of high molecular weight polymer having extracellular matrix modulators, saccharides, and synthetic peptides, for example:
Wound irrigations to prevent tumor local recidives on the surgical wound are disclosed; there is no mention therein about a preventive action against distant metastases.
As is well known in the art, metastases are lesions arising from a cancer mass, which have no contiguity relationship with the tumor from which they originate. The process by which malignant cells leave their primary site to disseminate throughout the body has become one of the main goals of cancer research with broad applications of great significance from a medical viewpoint.
The capacity to produce metastases is an attribute that distinguishes malignant neoplastic cells from benign tumor cells; malignant neoplastic cells can be released from the primary tumor and survive a complex series of interactions with the normal tissues and cells of the host, finally settling on a distant site. The overall phenomenon is triggered when cancer cells invade and occupy adjacent tissues, penetrating into body cavities and into circulation.
U.S. Pat. No. 4,588,587 (EP 263608) discloses metastasis inhibition in mammals by the administration of a natural protein extract with anti-coagulating and anti-proteolytic properties, obtained from the leech salivary gland. This extract would block tumor cell passage from circulation into other anatomic compartments. As this is a scarcely characterized natural extract, there is no defined pharmacological data available and no accurate process has been proposed to prevent the occurrence of metastatic spread during cancer surgery. Furthermore, its enhanced anticoagulant activity limits the application thereof during surgical manipulation because of the eventual risk of severe bleeding.
The process of invasion and metastasis via the blood stream includes a series of sequential stages which gave rise to the concept of a xe2x80x9ccascadexe2x80x9d phenomenon. The different steps follow a certain order and they are vital for a cancer cell to disseminate towards possible target organs (I. J. Fidler, Cancer Metastasis. Br. Med Bull. 1991, 47:157-77). First, the development and organization of new blood vessels on the increasing tumor mass take place. Then, cancer cells adhere to the new vessel walls, destroying their supportive matrix architecture and gaining access to the circulatory stream (P. Mignatti, D. B. Rifkin, Biology and Biochemistry of Proteinases in Tumor Invasion, Physiol. Rev. 1993, 73:161-95). Tumor cells are then passively carried to secondary implantation sites. Finally, they stop and become adhered to the vascular endothelium, they extravasate and start their proliferation again to form a metastatic focus.
While metastatic and tumoral invasion determine, in the end, the biological aggressiveness and the progression of the disease, most conventional therapeutic strategies are based on proliferation inhibition or on the destruction of neoplastic cells, and not on the reduction of the invasive or the metastatic properties thereof. In order to achieve a therapeutical action through the use of chemical agents or radiotherapy, it is necessary for the patient to undergo dosages that elicit clinical symptoms of toxicity. Unfortunately, this toxic action is not restricted to the growing tumor cell population and also affects fast renewing normal tissues, as well as epithelia and hematopoietic tissue.
Thus, the creation of new treatment strategies based on the interruption of metastatic dissemination is crucial.
Tumor cell spread towards circulation during surgical manipulation of a neoplastic mass was confirmed in experimental animal models and the implications of these results for the surgery of patients affected with cancer was broadly discussed for a long time from an empirical viewpoint.
Recently, the presence of circulating tumor cells in blood samples taken from the veins of patients subjected to breast cancer surgery was studied by Reverse Transcription and Polymerase Chain Reaction (RT-PCR) (D. C. Brown, A. D. Purushotham, G. D. Birnie, W. D. George, Detection of Intraoperative Tumor Cell Dissemination in Patients With Breast Cancer Using Reverse Transcription and Polymerase Chain Reaction. Surgery 1995, 117:95-101). This methodology, based on the specific mammary markers DF3 y CK 8, achieved sensitivity to detect 10 tumor cells in 5 ml of blood. The results confirmed the presence of cancer cells in blood during the surgical act with cells progressively disappearing from circulation.
These observations confirm for the first time the need to have adjuvant therapeutical strategies to minimize metastatic dissemination during the surgical manipulation of solid neoplasms.
During hematogenous metastasis, the tumor cell embolus must survive transportation into the blood stream, to become adhered later to a blood vessel and invade its wall. The vast majority of tumor cells are rapidly eliminated in the circulation, even if the aggregation of cells together, with blood platelets, or the formation of a fibrin network in the embolus, increase the chances of survival (V. Constantini, L. R. Zacharski, The Role of Fibrin in Tumor Metastasis, Cancer Metastasis Rev. 1992, 11:283-90; L. Weiss, F. W. Orr, K. V. Honn, Interactions of Cancer Cells With the Microvasculature During Metastasis, FASEB J. 1988, 2:12-21).
Publication WO 9217492, discloses new RGD (Arg-Gly-Asp) or KGD (Lys-Gly-Asp) peptides which inhibit platelet aggregation and adhesion-molecule receptors, suggesting the potential usefulness thereof in atherosclerosis, coronary, disease, phlebitis or cancer. The reference to the use in cancer is rare and is oriented to the reversion of coagulation disorders associated to the disease rather than limiting metastases.
Recently, we have examined the effects of different, neuropeptidic hormones and synthetic derivatives thereof on our mammary carcinoma murine model F3II (D. F. Alonso, G. Skilton, H. G. Farina, M. S. De Lorenzo, D. E. Gomez, Modulation of Growth and Urokinase Secretion by Vasopressin and Closely Related Nonapeptides in Metastatic Mouse Mammary Tumor Cells. Int. J. Oncol. 1997, 10:375-79). We have reported that vasopressin and its synthetic analog, desmopressin, significantly affect the behavior of these neoplastic cells in culture in vitro. It was found that in concentrations within a physiological range (100 ng/ml at 1 xcexcg/ml), these peptides are able to modulate breast cancer cell proliferation and urokinase secretion, a plasminogen-activating enzyme with profibrinolytic activity, involved in the metastasis via the hemal route.
In addition, according to Gader et al., desmopressin stimulates endothelial release of fibrinolytic system effectors, including the plasminogen tissue activator, the urokinase, and the specific inhibitor PAI-1 (A. M. A. Gader, J. Da Costa, J. D. Cash, A New Vasopressin Analogue and Fibrinolysis, Lancet 1973, ii: 1417-18). The activation of the plasminogen in plasmin generates the lysis of circulating fibrin clots. This fibrinolysis activation becomes complemented by the hemostatic effect of desmopressin, which effect is linked to an increase of plasmatic levels of coagulation factor VIII and of the von Willebrand factor (P. M. Mannucci, M. Aberg, I. M. Nilsson, B. Robertson, Mechanism of Plasminogen Activator and Factor VIII Increase After Vasoactive Drugs, Br. J. Haematol. 1975, 30:81-93).
1-Deamino-8-D-arginine-vasopressin, also referred to as desmopressin, is a synthetic analog of the antidiuretic hormone, vasopressin. The antidiuretic hormone (ADH) vasopressin is released by the posterior hypophysis or neurohypophysis. It performs an important role in the regulation of urine concentration and in the maintenance of body fluids. In addition, it can regulate blood circulation by means of its potent vasopressor effect.
Vasopressin is a nine amino acid peptide closely related in structure to another neurohypophysis hormone, oxytocin. The structure of vasopressin is well preserved, as it is identical in all mammals:
pigs being the exception where the arginine in the -8 position is replaced by lysine. Cysteine residues form a disulfide bridge between the -1 and the -6 position, which is essential for the biological activity of all these nonapeptides (V. du Vigneaud, D. T. Gish, P. G. Katsoyannis, A Synthetic Preparation Possessing Biological Properties Associated With Arginine Vasopressin. J. Am. Chem. Soc. 1954, 76:4751-52).
A synthetic analog of vasopressin, that is 1-deamino-8-D-vasopressin: Sxe2x80x94CH2xe2x80x94CH2xe2x80x94COxe2x80x94Tyrxe2x80x94Phexe2x80x94Glnxe2x80x94Asnxe2x80x94Cysxe2x80x94Proxe2x80x94DArgxe2x80x94GlyNH2, the so-called desmopressin, was prepared for the first time by the end of the 1960s (M. Zaoral, J. Kole, F. Sorm, Amino Acids and Peptides, LXXI, Synthesis of 1-Deamino-8-D-Aminobutyrine-Vasopressin, 1-Deamino-8-D-Lysine-Vasopressin, and 1-Deamino-8-D-Arginine-Vasopressin, Coll. Czech. Chem. Commun. 1967, 32:1250-57). Deamination in the -1 position provides the molecule with enhanced resistance to peptidase degradation; the inclusion of D-arginine in the -8 position reduces its pressor effect and strengthens its antidiuretic action.
Desmopressin possesses a much longer half-life and pharmacological action in vivo than the naturally occurring peptide. These properties make desmopressin the preferred agent in the treatment of diabetes insipidus, which disease is due to an inadequate hypophysial secretion of vasopressin.
In view of the modulator properties of desmopressin on the behavior of tumor cells and the action thereof on the circulating fibrinolytic system, in accordance with the prior art previously described, the Applicants have researched the ability of desmopressin to alter the metastatic cascade in an animal model of solid tumor metastatic dissemination. The model reproduces the massive release of cancer cells into the circulating stream which could take place during surgical manipulation of a neoplastic mass.
The results obtained unexpectedly show for the first time the inhibition of lung metastatic colonization by mammary tumor cells through the application of desmopressin, making possible the availability of a medication useful to minimize metastatic dissemination during breast cancer surgery.
However, this action might be exerted on any other malignant solid tumor with metastatic potential disseminating in blood circulation. In particular, those carcinomas and adenocarcinomas originating from organs capable of inducing peritumoral fibrin deposition and which are subject to intravascular transportation.
It is an object of the present invention to use 1-deamino-8-D-arginine vasopressin (desmopressin) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing any of them, in the preparation of a medication which inhibits metastatic dissemination in a second organ by metastatic tumor cells spread during the surgery of a cancerous tumor in a first organ.
Preferably, it is an object of the invention to use 1 -deamino-8-D-arginine vasopressin (desmopressin) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing any of these, in the preparation of a medication which inhibits metastatic dissemination in lungs by metastatic cells disseminated during breast cancer surgery.
It is still another object of the invention to provide a pharmaceutical composition which inhibits metastatic dissemination in a second organ by metastatic tumor cells spread during the surgery of a cancerous tumor in a first organ, comprising 1-deamino-8-D-arginine vasopressin (desmopressin) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent.
Preferably, it is an object of the present invention to prepare a pharmaceutical composition which inhibits lung metastatic dissemination by metastatic tumor cells spread during the surgery of a cancerous breast tumor, comprising 1-deamino-8-D-arginine vasopressin (desmopressin) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent.
It is also an object of the present invention to prepare a pharmaceutical composition which inhibits metastatic dissemination in a second organ by metastatic tumor cells spread during the surgery of a cancerous tumor in a first organ, comprising the formulation of 1 -deamino-8-D-arginine vasopressin (desmopressin) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent.
Another object of the present invention is to prepare a pharmaceutical composition which inhibits lung metastatic dissemination by metastatic tumor cells spread during the surgery of a cancerous breast tumor, comprising the formulation of 1-deamino-8-D-arginine vasopressin (desmopressin) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent.
Furthermore, another object of the present invention is a method to inhibit mammal metastatic dissemination in a second organ by metastatic tumor cells spread during the surgery of a cancerous tumor in a first organ, comprising the administration by injection of a therapeutically effective amount of 1-deamino-8-D arginine vasopressin (desmopressin) or a pharmaceutically acceptable salt thereof to the mammal, together with a pharmaceutical composition containing any of those.
Even more preferably, the object of the present invention is based on a method to inhibit lung metastatic dissemination in mammals by metastatic tumor cells spread during the surgery of breast cancer, comprising the administration by injection,of a therapeutically effective amount of 1-deamino-8-D arginine vasopressin (desmopressin) or a pharmaceutically acceptable salt thereof to the mammal, together with a pharmaceutical composition containing any of those.
1-Deamino-9-D-arginine vasopressin (desmopressin) can be preferably used in the form of a pharmaceutically acceptable salt. For the purpose of the present invention, desmopressin acetate is preferably used.